A relationship between dopamine D2 receptor blockade in the brain and the antipsychotic effects of neuroleptics has been demonstrated. The site of action of neuroleptics, i.e. which cerebral dopaminergic system(s) or subset of D2 receptors, and the relationship between changes in dopaminergic function and the pathophysiology of schizophrenia are not known. While autopsy studies have reported increased receptor numbers in the striatum and nucleus accumbens in man, in vivo studies of striatal D2 receptor in schizophrenic subjects have given conflicting results. The ligands which are presently used in PET studies of the D2 receptor, i.e. spiperone or raclopride,are unsuitable for studies of limbic or cortical receptors. Raclopride may not be suitable for measurement of striatal D2 receptor numbers because of competitive displacement by endogenous dopamine. Our group has synthesized and studied iodinated benzamides with relatively low lipophilicity, very high affinity (KD = 25 picomolar), and selectivity for the D2 receptor that can be used to label limbic cortical and striatal D2 receptors in vitro and in vivo. Using a careful analysis of structure-activity relationships for substituted benzamides and the knowledge we have gained in relating receptor affinity and lipophilicity to in vivo brain uptake, we propose a series of fluorinated benzamides which should have very high potency and selectivity for the D2 receptor as well as optimal lipophilicity for in vivo studies. Unlabelled ligands will be synthesized and preliminary evaluation performed by determination of IC50's for inhibition of [3H] spiperone and [125I] epidepride binding to striatal membranes and log KW pH 7.5 Ligands with high affinity and optimal lipophilicity will be radiolabelled with 18F. In vitro pharmacological characterization of their binding in striatum, limbic regions and cortex will be performed to establish their potency and specificity for the D2 receptor. In vivo studies of brain biodistribution rats and monkeys will be performed to examine their suitability as ligands for the in vivo study of striatal and extrastriatal D2 receptors in man and to validate the use of tracer kinetic models needed to measure receptor function in vivo. The availability of these ligands, proper tracer kinetic models, and very high resolution PET scanners (FWHM < 3 mm) should allow study of limbic and cortical as well as striatal D2 receptors in schizophrenic subjects, and patients with dopaminergic related disorders.